The cytokine midkine and its receptor RPTP? regulate B cell survival in a pathway induced by CD74.

ABSTRACT: Lasting B cell persistence depends on survival signals that are transduced by cell surface receptors. In this study, we describe a novel biological mechanism essential for survival and homeostasis of normal peripheral mature B cells and chronic lymphocytic leukemia cells, regulated by the heparin-binding cytokine, midkine (MK), and its proteoglycan receptor, the receptor-type tyrosine phosphatase ? (RPTP?). We demonstrate that MK initiates a signaling cascade leading to B cell survival by binding to RPTP?. In mice lacking PTPRZ, the proportion and number of the mature B cell population are reduced. Our results emphasize a unique and critical function for MK signaling in the previously described MIF/CD74-induced survival pathway. Stimulation of CD74 with MIF leads to c-Met activation, resulting in elevation of MK expression in both normal mouse splenic B and chronic lymphocytic leukemia cells. Our results indicate that MK and RPTP? are important regulators of the B cell repertoire. These findings could pave the way toward understanding the mechanisms shaping B cell survival and suggest novel therapeutic strategies based on the blockade of the MK/RPTP?-dependent survival pathway.

SUBMITTER: Cohen S 

PROVIDER: S-EPMC3244541 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature